Peptides, as therapeutic agents, have several advantages in clinical applications due to their low toxicity and high specificity (Bellmann-Sickert and Beck-Sickinger, 2010). Recently the US Food and Drug Administration (FDA) approved several peptide drugs including Enfuvirtide that inhibits HIV entry into cells, Exenatide that stimulates insulin secretion in type 2 diabetes patients and several peptides for treatment of cancer (Bellmann-Sickert and Beck-Sickinger, 2010). Despite these advantages, therapeutic peptides have several limitations. They are highly prone to proteolytic degradation during storage or when used for oral administration (McGregor, 2008) and require parenteral administration. In addition, these peptides need cold storage due to short shelf life after purification or chemical synthesis. Moreover, repeated injections are often needed but this decreases patient compliance (Hamman and Steenekamp, 2011). Therefore, it has been discovered herein that there is a great need for exploration of less expensive and patient-friendly drug delivery methods.
Type 2 diabetes is caused by combination of beta cell dysfunction and insulin resistance (Scheen, 2003). It is predominantly diagnosed in adults and responsible for 90-95% of the existing diabetic cases (National diabetes fact sheet, 2011). Surplus production of hepatic glucose and reduced uptake of glucose also contribute to excess blood sugar levels (Scheen, 2003). The type 2 diabetic patients exhibit belittled incretin effect, which requires insulin secretion in response to high glucose in the blood (Scheen, 2003). Diabetes is a global rising problem. According to the national diabetes fact sheet 2011, the total cost associated annually for treatment and management of diabetes in the US is $116 billion whereas the indirect costs associated with loss of work, disability and other factors was $58 billion adding up the total cost to $174 billion. The treatment for diabetes includes either oral drugs (small molecules) with or without insulin injections. Globally, the prevalence of diabetes is estimated to escalate from 171 million in 2000 to 366 million in 2030 (Davidson, 2009), which could double the associated costs. Diabetes is a major health and economic burden on society (Wild et al., 2004) and therefore the cost of treatment of diabetes should be addressed.
GLP-1 is a peptide hormone secreted by the L cells of the intestine that stimulates the secretion of insulin from the pancreas (Chia et al., 2005). It has been shown to play an important role in increasing the beta cell mass and has potent antidiabetic effects associated with weight loss (Baggio and Drucker, 2007). But GLP-1 has a very short half-life of less than 2 min because it is degraded by the dipeptidyl peptidase IV (DPP-IV) serum enzyme into biologically inactive form, thereby lowering the incretin action of the peptide (Kieffer et al., 1995). Thus, it is disclosed herein that DPP-IV resistant GLP-1 analogs are needed for treatment of the type 2 diabetes.
EX4 is a DPP-IV resistant analog of GLP-1 with higher binding efficacy to the mammalian GLP-1 receptor than GLP-1 and functions as an effective agonist (Young et al., 1999). EX4 modulates the glucose level in a glucose dependent manner and increases the sensitivity to insulin and has shown promising biological activities in vivo for treating type 2 diabetes (Young et al., 1999). Exenatide, a synthetic EX4 is the first drug that carries out the function of incretin to be approved by FDA for glycemic control, along with an oral antidiabetic medication. Exenatide is used in injectable form and requires cold storage and sterility. In addition, the requirement for multiple injections decreases patient compliance. Thus, it is disclosed herein that there is a need for alternative methods of production and delivery of EX4 or other therapeutic proteins to reduce the cost and increase patient compliance.